The neurophyseal hormones vasopressin (VP) and oxytocin (OT) are cyclic nonapeptides secreted by the posterior pituitary gland.
Only one OT receptor has so far been well characterised, while three VP receptors are known. These are designated the V1a, V1b and V2 receptors.
Vasopressin acts on the blood vessels, where it is a potent vasoconstrictor, and on the kidneys, where it promotes water reuptake leading to an antidiuretic effect.
The V1a, V1b, and V2, as well as the OT receptors, are members of the super-family of seven transmembrane receptors known as G-protein coupled receptors. The V1a receptor mediates phospholipase C activation and intra-cellular calcium mobilisation. Localisation of the receptors includes blood platelets, blood vessels, hepatocytes, brain and uterus-cervix. Thus a V1a antagonist may have effects on any or all of these tissues. For example, selective V1a antagonists have been cited as having clinical utility in dysmenorrhoea, pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.
With respect to dysmenorrhoea it has been proposed that myometrial activity is markedly increased in women with dysmenorrhoea during menstruation. It is proposed that the myometrial ischemia caused by increased uterine contractility might explain the menstrual pain. Furthermore, on the first day of menstruation, higher plasma concentrations of vasopressin have been measured in dysmenorroeic women than in controls.
In healthy women without dysmenorrhoea, intravenous infusion of lysine-vasopressin resulted in decreased uterine blood flow, increased uterine contractility and slight to moderate dysmenorrhoea-like pain, these effects being inhibited by a selective human V1a receptor antagonist. (Bossmar, T. et al., BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY (1997 April), 104(4), 471-7). Also, it is known that vasopressin contracts human uterine arteries in a dose-dependent and V1a-mediated fashion.
The above evidence suggests that a V1a antagonist would be an appropriate and effective treatment for dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea). Further evidence is taken from the clinical study carried out on the selective V1a antagonist SR49059 (“Effect of SR49059, an orally active V1a vasopressin receptor antagonist, in the prevention of dysmenorrhea”. Brouard, R. et al., BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY (2000), 107(5), 614-619). It was found that there was a dose-related decrease in pain and a dose-related decrease in the amount of additional pain-killer taken compared to patients taking placebo.
The International Patent Application WO 03/016316 A1, published 27 Feb. 2003, discloses a number of compounds which are claimed to be oxytocin agonists and to find use in the treatment of male erectile dysfunction. No V1a antagonist activity is reported. The European Patent Application EP 1 449 844 A1, published 25 Aug. 2004, discloses a number of compounds which are claimed to be V1a antagonists and to find use in the treatment of primary dysmenorrhoea.
There exists a need for treatments for conditions which are associated with the V1a receptors. There further continues to exist a need for alternative Via antagonists. Simple synthesis and oral availability are additional desirable characteristics.